1. Field of the Invention
Subject of the invention is an antibiotic/s containing bone substitute material with sustained active substance release.
2. Description of Related Art
Osteomyelitis is an infection of the bone tissue which is very difficult to therapy. Normally, the treatment comprises the debridement of infected bone areas. Subsequent localized antibiotics therapy has proven well, with non-resorbable Septopal® chains or with gentamicin-containing collagen fleeces. Here, gentamicin is locally released in high doses which kills off the remaining bacterial pathogens. Desirable is a bone substitute material which, on one hand, can locally release antibiotics and, on the other hand, will further bone growth and which has a placeholder function.
The use of calcium sulfate dihydrate as a bone substitute material has been known for a long time (E. Martin: Zur Ausfüllung von Knochenhöhlen mit totem Material. Zentalb Chir 21 (1894) 193-200; E. Edberg: Some experiences of filling osteous cavities with plaster. Acta Chir Scand 67 (1930) 313-319; J. O. Hollinger, J. Brekke, E. Kruskin, D. Lee: Role of bone substitutes. Clin Orthop 324 (1996) 55-65).
The US 2002110541, U.S. Pat. No. 5,807,567, US 2002197315, U.S. Pat. No. 6,652,887, U.S. Pat. No. 5,756,127 and U.S. Pat. No. 5,614,206 describe bone substitute materials which essentially consist of a mixture of α and β calcium sulfate and are to be used as drug delivery systems for pharmaceutically active substances. These bone substitute materials release the major amount of the incorporated active substance in the first hours after introduction of the material into an aqueous solution and, thereafter, only minor amounts of active substance will be released over a period of several days.
DE 19953771 discloses a bone substitute material consisting of a mixture of calcium sulfate dihydrate and nano-particular hydroxyl apatite. Moulds of this material have a high interior surface and can be impregnated with aqueous antibiotic solutions. Such treated moulds will have a more or less sustained release action. The major amount of the antibiotic will be released in the first hours. The sustained release is due to the adsorption of the active substance on the interior surface of the mould.
DE 10114244, DE 10114245, DE 10114364, DE 10227914 or DE 10227938 describe active substance formulations or, respectively, methods for the manufacture of these active substance formulations which rely on the formation or, respectively, use of active substance salts of low solubility in water. Thus, DE 10227914 discloses a pharmaceutical preparation with a sustained active substance release, consisting of mixtures of powdered teicoplanin and at least one powdered, water-soluble salt form of gentamicin, clindamycin, vancomycin, moxifloxacin, and ciprofloxacin and an inorganic auxiliary substance and/or organic auxiliary substance. Proposed as auxiliary substances are, inter alia, calcium carbonate, calcium sulfate dihydrate, tricalcium phosphate and hydroxyl apatite. The pharmaceutical preparation will be used in the form of pellets, moulds, fibers/threads and granulates as implant material.
DE 10227935 describes an antibiotic coating of porous bodies and their utilization. In the pore system of non-metallic and metallic porous bodies, a coating is provided of at least one antibiotic salt—with low solubility in water—from the group of the fatty acid salts and dodecyl sulfates of netilmicin, sisomycin, gentamicin, clindamycin, amikacin, kanamycin, tobramycin, ciprofloxacin, and vancomycin. The coating is also applied on porous powders, porous granulates, porous moulds and porous layers of compact bodies. The antibiotically coated bodies are to be used as implants.
U.S. Pat. No. 5,055,307 proposes granulates for sustained active substance release. These granulates are formed of a calcium phosphate with a substance volume ratio of Ca to P from 1.3 to 1.8, having a porosity of 0.1% to 70% and a specific surface of 0.1 m2/g to 50 m2/g. The pore size is in the range from 1 nm to 10 μm. The granulates are formed in a calcination process in a temperature range from 200° C. to 1,400° C. Subsequently, the granulates are impregnated with an active substance. It is also possible to drench the granulates with a polymer solution and separate a polymer layer on the granulates.